This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Understanding skeletal muscle metabolism at rest and during exercise is fundamental to human physiology as well as evaluation of patients with weakness. Two activities are directed by the neurology group at Presbyterian. (1) Myopathies Metabolic myopathies due to inborn errors of muscle energy metabolism (including defects in carbohydrate, lipid and mitochondrial metabolism) are common genetic defects that cause a variety of symptoms such as fatigability, weakness and rhabdomyolysis. Exercise testing and muscle biopsy are standard procedures for diagnosis of metabolic myopathies. The concentration of metabolites in skeletal muscle such as creatine and lipids in the intra- and extracellular compartments are relevant to understanding muscle metabolism. Standard biopsy methods are unattractive because of obvious problems: they are invasive and only a small skeletal compartment may be examined. Magnetic resonance (MR) methods allow direct measurements of metabolites as well as detection of intracellular lipids (proton-MR-spectroscopy). There is a considerable controversy interpretation of these data, in part because of low sensitivity and overlap from key signals. All prior studies have been performed in instruments operating at 1.5 to 3 Tesla (T). In principle, higher fields of 7T provide more signal and much better resolution, i.e. less overlap between signals. Initial studies of the leg at 7T in healthy subjects and pilot studies with metabolic myopathie patients have been successful. The purpose of this project is to determine whether proton-MRS at high-field 7T is a valuable technique for non-invasive diagnosis and monitoring of metabolic myopathies. (2) Skeletal Muscle Metabolism during Exercise The overall goal of this study is to determine the safety and efficacy of endurance exercise training as therapy and the potentially adverse effects of habitual physical inactivity in patients with skeletal muscle mitochondrial electron transport chain defects due to heteroplasmic mitochondrial DNA mutations. Specific Aims: 1) To establish that in patients with mtDNA defects, endurance training induces mitochondrial proliferation whereby increases in wild-type mtDNA levels offset high levels of mutant mtDNA in individual muscle cells, thereby improving mitochondrial oxidative capacity and ultimately exercise performance and quality of life;and to determine effects of endurance training on cardiac function and capillary formation in skeletal muscle;2) In these patients, to establish the effects of prolonged physical inactivity (normally associated with down-regulation of mitochondrial volume) on levels of mutant mtDNA and oxidative capacity in muscle and upon cardiac function and capillary levels in skeletal muscle. Research Design: Patients will undergo physiological exercise testing, cardiac evaluation and muscle needle biopsy and then be randomized to regular exercise training or no training for 6 months with retesting at the end of that time;then untrained patients will train and trained patients detrain for 6 months with repeat testing at the end of that time;thereafter, patients will be encouraged to train for an additional 1 year with retesting at the end of that period. Training and detraining effects on mitochondrial genotype and function will be determined by changes in copy number of mutant and wild-type mtDNA;these genetic changes will be correlated with respiratory complex enzymatic activity and assembly in individual muscle cells or homogenate. Training effects on muscle and cardiovascular function will be assessed by monitoring peak work, oxygen utilization, cardiac output and stroke volume in cycle exercise, and by monitors of quality of life. Given the prevalence of mitochondrial myopathies attributable to mitochondrial DNA mutations, the current lack of any effect therapy, and the possible negative effects of physical inactivity on muscle oxidative capacity, there is an immediate need to define appropriate recommendations for exercise training in patients with mitochondrial electron transport chain defects.